She was good nature and pliable and was well matched with her husband. Theirs was a happy marriage that produced thirteen children. María Isabella lacked political acumen and had no ambitions, but unlike her powerful mother in law, Maria Carolina of Austria, she was popular. In 1825 her husband ascended to the throne as King Francis I of the Two Sicilies. During his reign, she did not play any political role, but was well liked for her simple manners and generosity. She visited her native Spain in 1830 when her second daughter Maria Christina married King Ferdinand VII of Spain. Shortly after their return to Naples, her husband died in November 1830.

As a Queen mother, she remained a popular figure. Her eldest son, Ferdinand II of the Two Sicilies, was deferential towards her, but her efforts to obtained a pardon for her second son, the
Prince of Capua, were fruitless. In 1839, with Ferdinand II's approval, she contracted a morganatic marriage. She died on 13 September 1848 at age 59.